Metabolically stressful conditions, including inflammation and hypoxia characteristic of solid tumors, asthma and other pathological conditions, result in dramatic increases in extracellular concentrations of adenosine. Differentiation and functionality of immune cells critically depend on the microenvironment and under certain conditions tumor-infiltrating immune cells can benefit tumor by producing factors promoting angiogenesis and suppressing immunity. We have preliminary data demonstrating that stimulation of adenosine receptors skews dendritic cell (DC) differentiation from normal immune protective phenotype toward immune suppressive DC with pro-angiogenic and tumor-growth promoting properties. We also identified adenosine as an important metabolite inducing secretion of angiogenic factors including vascular endothelial growth factor (VEGF) by tumor immune infiltrate and identified A2B receptor as a mediator of the observed effects. The profound effect that signaling through A2B receptor has on differentiation and cytokine secretion by tumor infiltrating immune cells and tumor angiogenesis, identify A2B adenosine receptor as an important therapeutic target. Adenosine shapes tumor microenvironment through regulation the cytokine production by hematopoietic cells via both A2 (A2A and A2B) adenosine receptor-mediated signaling. Thus, we also propose the studies allowing to discriminate between the roles of A2A and A2B receptors in regulation the functions of tumor-infiltrating immune cells. We hypothesize that adenosine signaling through A2B receptor on host tumor-infiltrating immune cells benefits tumor growth and that therapeutic blockage of A2B and A2 receptor signaling will produce improved clinical outcome and benefit anti-tumor immunity. Using genetically modified and bone marrow chimeric mice, we intend to: 1) Determine the functional significance of A2B and A2A/A2B receptor in cancer; 2) Determine whether A2 receptor-mediated VEGF production by hematopoietic cells benefits tumor growth and angiogenesis; 3) Determine the efficacy of therapy targeting A2B and A2 receptor signaling on tumor growth and vacularization, tumor-infiltrating immune cells, and immune responses. The anticipated data will lay the foundation for the future clinical trials of adenosine receptor antagonists and would have implications for the development of novel therapeutic modalities for cancer and immunotherapies. PUBLIC HEALTH RELEVANCE: The purpose of this study is to determine the role of adenosine signaling mediated via A2 adenosine receptor in aberrant differentiation and activation of tumor infiltrating myeloid cells, induction of immune suppression and tolerance and promoting tumor growth and vascularization. The important question of whether therapeutic blockage of A2 receptor signaling can produce improved clinical outcome and benefit anti-tumor immunity and whether adjuvant application of such therapy can enhance the efficacy of anti-angiogenic will be addressed. The anticipated data will lay the foundation for the future clinical trials of adenosine receptor antagonists and would have implications for the development of novel therapeutic modalities for cancer, anti-angiogenic and immunotherapies in particular.